CN1135388C - Multilayer reagent test strip and method for testing using same - Google Patents

Multilayer reagent test strip and method for testing using same Download PDF

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CN1135388C
CN1135388C CNB971297886A CN97129788A CN1135388C CN 1135388 C CN1135388 C CN 1135388C CN B971297886 A CNB971297886 A CN B971297886A CN 97129788 A CN97129788 A CN 97129788A CN 1135388 C CN1135388 C CN 1135388C
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detector bar
sample
chemical examination
film
analyte
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CN1202620A (en
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J
J·道格拉斯
E·基瑟尔
M·F·托马斯科
R·达托
E·G·赖克
К
D·P·托海
�������ɭ
M·马克森
Z·维特科
S·瑟格克
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LifeScan Inc
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/66—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood sugars, e.g. galactose
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/54—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving glucose or galactose
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/52—Use of compounds or compositions for colorimetric, spectrophotometric or fluorometric investigation, e.g. use of reagent paper and including single- and multilayer analytical elements
    • G01N33/521—Single-layer analytical elements
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/52—Use of compounds or compositions for colorimetric, spectrophotometric or fluorometric investigation, e.g. use of reagent paper and including single- and multilayer analytical elements
    • G01N33/521—Single-layer analytical elements
    • G01N33/523—Single-layer analytical elements the element being adapted for a specific analyte
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/52—Use of compounds or compositions for colorimetric, spectrophotometric or fluorometric investigation, e.g. use of reagent paper and including single- and multilayer analytical elements
    • G01N33/525—Multi-layer analytical elements
    • G01N33/526—Multi-layer analytical elements the element being adapted for a specific analyte

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Abstract

A multi-layer reagent test strip measures the concentration of an analyte in a biological fluid coated thereon. The sample is directed to a plurality of assay zones arranged along the test strip where the analyte reacts with the reagent to change color. Each assay zone also contains an inhibitor of the color change reaction. The inhibitor concentration increases in successive assay zones; the measurement of the analyte concentration is thus given by the number of discolored assay areas. The test strip is particularly useful for measuring glucose in a whole blood sample. In a preferred embodiment the sample is directed to the assay site, i.e. the non-compressed area of the membrane, along a path formed by selective compression of the area of the membrane.

Description

Multilayer reagent detector bar and the method for using it to detect
Technical field
The application is the part continuation application of No. 08/743432 unsettled U. S. application of submission on November 1st, 1996, this application be submit to August 3 nineteen ninety-five, the continuation application of existing resigned No. 528511 applications, this application is again the part continuation application that No. 411238 applications of submitting to March 27 nineteen ninety-five and No. 442035 of submitting to May 15 nineteen ninety-five are applied for.
The present invention relates to a kind of dry detector bar of measuring analyte concentration in the biological fluid; More particularly, be a kind of detector bar that instrument can directly be measured concentration that need not.
Background technology
There is multiple visual inspection apparatus to be developed out and to be used for the measurement of concetration of some analyte of biological fluid.These devices are the concentration of glucose, cholesterol, dawn white matter, ketone, phenylalanine or the enzyme in energy measurement blood, urine or the saliva for example.
But the concentration of glucose with combining based on the dried phase reagent bar detection of biological body fluid sample of the composition of enzyme extensively is used in clinical labororatory, doctor's clinic, hospital and the family.In fact, reagent strip has become necessity every day of a lot of people among the hundreds of diabetics of the U.S..Because diabetes can cause abnormal response dangerous in the blood chemistry, cause visual deprivation, renal failure and other medical consequences then.For the risk that makes these consequences is reduced to minimum, most diabetes patients must regularly carry out the oneself and detect, and regulate their concentration of glucose then in view of the above, for example can be by keeping on a diet and/or the method for insulin injection is regulated.Some patients must reach four every day or more blood sugar concentration detects.
The diabetic must keep on a diet with the intake of regulating sugar and/or arrange the injection of insulin properly, they also must often detect blood sugar concentration for this reason, therefore particularly importantly have to measure the quick, inexpensive of glucose and reagent strip accurately concerning them.
Known reagent strip all contains a kind of indication example, and it can show different tones according to the difference of concentration of glucose in the biological fluid that is coated on the reagent strip.Although used the reduction chemical reaction in the some of them reagent strip, in the reagent strip more general also relate to oxidable dyestuff or dyestuff right.Some reagent strips comprise a kind of enzyme, and as glucose oxidase, it can be glucose enzyme and hydrogen peroxide with glucose oxidase.They also contain a kind of oxidable dyestuff and a kind of material with peroxidating activity, the oxidation reaction of the latter's oxidable dyestuff of selectivity catalysis in the presence of hydrogen peroxide.No. 5306623, United States Patent (USP) people such as Kiser, that announce on April 26th, 1994 (for example referring to)
A kind of direct measurement biological fluid composition is disclosed in No. 3964871, the United States Patent (USP) that Hochstraser announced on June 22nd, 1976, as the disposal type bar of concentration of glucose.The concentration of this bar record component, it had both comprised a kind of indicator, and was oxidized and variable color also comprises a kind of " antagonist " when with composition to be measured reaction, before being fallen by full consumption, can prevent the accumulation of oxidized indicator to a certain extent.
People such as Palmer on May 24th, 1989 disclosed european patent application disclose and disclose a kind of glucose " numeral " quantified system analysis No. 5036000, United States Patent (USP) (also see announced on July 30th, 1991) in No. 0317070.The method of organic compound substrate concentration is at first with a kind of substrate-specific oxydasis compound that is applied in this systematic survey biological fluid, produces hydrogen peroxide.This system comprises a chromophore, and it is stable hydrogen-peroxide reduction agent in a kind of reductive agent of hydrogen peroxide and a kind of air, has bigger reduction potential.Before stable process hydrogen oxide reductive agent is consumed in first kind of air, the bigger reduction potential that it had postponed by chromophore cause can detected metachromasia.If therefore concentration of hydrogen peroxide to be measured is lower than the predeterminated level corresponding to superoxide hydrogenase concentration stable in the air, just there is not metachromasia to take place.Consequently, systematic quantification has been measured concentration, and does not rely on variable color intensity.
A kind of detector bar that analyte is measured that is used for one deck carrier film is disclosed in No. 4738823, the United States Patent (USP) that Englemann announced on April 19th, 1988, be fixed with a kind of absorbing material on this carrier film, it can remove the excessive sample that is coated on the detector bar.Detector bar also can comprise an overlayer, and it has in order to introduce the opening of sample.
A kind of device of measuring analyte concentration in the liquid sample is disclosed in No. 4810470, the United States Patent (USP) that people such as Burkhardt announced on March 7th, 1989.This device comprises the living matrix of one or more suctions, and this matrix is covered by a kind of liquid impervious coating or film.Sample is deposited on the somewhere of absorbent substrate, measures with the matrix chromatography.Sample arrives the chemical examination district by capillary action, and a kind of detectable of analyte is contained at this place.
Disclose a kind of chemical analysis pick-up unit in No. 4994238, the United States Patent (USP) that people such as Daffem announced on February 19th, 1991, but this device is made up of an absorption layer, a waterproof barrier layer and the reagent layer with detection volume.Sample is coated on the reagent layer by aperture aligned with each other on superjacent absorption layer and the barrier layer.
No matter detection be at home, in doctor's clinic, clinical in or in hospital, carry out, the accuracy of glucose detection and reproducibility all are vital.In the reagent strip of indication color, need change color obvious, and insensitive to the concentration change of the composition beyond the glucose in the biological fluid.In machine-readable detector bar, the absorbance log that variable color shows as under setted wavelength changes, although it also is very important concerning accuracy, but because the diabetic may have vision impairment, concerning them, have one according to concentration of glucose and significantly the visual observation agent bar of variable color is particularly important.
Owing to relate to series of chemical, variable color is not instantaneous generation.Therefore the user for the generation of reacting must wait the preceding paragraph time-be generally one minute or less than.If use the apparatus measures detector bar, timing circuit can provide signal, shows that reaction finishes.But if with the naked eye measure detector bar, do not have the help of instrument, perhaps the user has underestimated required time, too early number and draw incorrect result.Perhaps, perhaps the user must be necessary before reading etc. to finish to guarantee reaction the enough time, and the result causes unnecessary delay, makes the user unhappy.Therefore need a kind of " chemistry " timing agent, that is to say the composition in a kind of detector bar, glucose in its variable color and the sample (or other analyte of considering) concentration is irrelevant, and only is through after the enough time, has finished color producing reaction with sample variable color just takes place.
Summary of the invention
According to the present invention, the composition of measuring the lengthening multilayer reagent detector bar of analyte concentration in the biological fluid samples that is coated with thereon comprises
A) bottom, this bottom has a hole of accepting the perforation of sample;
B) rete, in the face of bottom simultaneously is the sample face, relative another side is a detection faces, this rete is distributed with a large amount of water absorptivity chemical examinations zone along its length direction, separated by non-suction zones each other, contain a kind of reagent that variable color can take place with the analyte reaction in the film, this reagent is formed and is comprised
I) react the first kind of composition that generates hydrogen peroxide with analyte;
Ii) with second kind of composition of hydroperoxidation generation variable color; With
The third composition that iii) suppresses second kind of composition variable color;
C) middle layer between bottom and rete;
D) measuring apparatus that makes sample distribute and come along detector bar, this device are formed and are comprised the fluid transhipment passage that is formed in the middle layer, and the guiding sample arrives water absorptivity chemical examination district through the film surface; Inhibitor concentration is raising in a predefined manner from detector bar first end a distance, therefore if variable color will take place, the also necessary corresponding rising of the analyte concentration that is contained in the sample, wherein after sample is coated on the detector bar, one or several chemical examination district's variable color, and indicate the concentration of analyte in the sample from first end transformation region farthest.
In the embodiment preferred, fluid transhipment passage is rectangular basically.
The method of operating step of measuring analyte concentration in the biological fluid samples comprises:
A) sample is coated on the reagent detector bar, this detector bar is formed and is comprised:
I) bottom, this bottom has a hole of accepting the perforation of sample;
Ii) rete, have a sample face in the face of bottom, this rete comprises a large amount of water absorptivitys chemical examinations district, and each chemical examination district is with contain after the liquid of the analyte of scheduled volume contacts at least all can variable color, the closer to detector bar first end, cause that the amount of the analyte of chemically examining district's variable color is many more;
Iii) measuring apparatus makes sample arrive each chemical examination district from through hole along predetermined non-suction path profile;
B) measure analyte concentration by observing from detector bar first end variable color chemical examination district farthest.
This detector bar is such one type, and it indicates contained analyte concentration in the biological fluid that is coated on the detector bar " sample face " visibly.As seen indicated number is in detector bar reverse side (or " detection faces ").
The chemical composition of detector bar is decided according to the analyte/biological fluid that will measure certainly.Detector bar can designed to be used the analyte in the biological fluid detection such as blood, urine, saliva and the water, as glucose or other carbohydrate, ethanol, cholesterol, protein, ketone, uric acid, phenylalanine or enzyme.For considering simply and easily, the reagent detector bar that detects glucose in the blood is disclosed in this instructions in detail.Those of ordinary skill in the art is easy to expect using it for the combination that detects other analyte/biological fluid from the disclosed information of this instructions.
Detector bar of the present invention provides the simple and rapid relatively method of measuring concentration of glucose in the blood sample to be measured.Detector bar is formed and is comprised a bottom, and bottom has a hole, and sample is introduced on the sample face of porous matrix by this hole, and the reverse side of sample face is a detection faces.Matrix generally is a kind of film, and two speech can exchange use in this instructions and claims.Detectable is added on the matrix, is immersed in more or less in the hole of matrix.Be easy meter, we are called " coating " with the reagent on the matrix sometimes in this instructions and appended claims, are meant coatings of reagent infiltration matrix.
The middle layer is between bottom and matrix.In one embodiment, arranging the non-suction zones of discontinuous film in the middle layer, the guiding sample enters a series of water absorptivity chemical examinations district that announces along detector bar.(used in this instructions and the appended claims " suction " means absorbefacient.) in the middle layer around the chemical examination district and above the space constraint sample flow that surrounds by a series of recesses to these zones.In another embodiment, have a lengthening to be actually the hole of rectangle in the middle layer, make sample arrive the continuous part of suction zones, suction zones is separated by a non-suction zones.
The point of the whole blood that the sample of certain volume-be generally comprises red blood cell and glucose-directly is in each zone in a series of chemical examinations district of membrane sample face.The poriness of matrix make fluid for example can be by capillary action from the sample surface current to detection faces.So glucose response in detectable and the blood, on the detection faces or near the generation variable color.Because the red blood cell color is dark, make the detection of variable color difficulty comparatively, so matrix optimization is anisotropic, promptly from the sample face to detection faces, the aperture is from diminishing greatly gradually, so that red blood cell promptly is being hunted down away from the detection faces place.There is multiple material to can be used as the various compositions of detector bar of the present invention and timing agent.The some of them material be disclosed in people such as Kiser respectively in the United States Patent (USP) of announcing on April 26th, 1994 and May 23 nineteen ninety-five 5306623 and No. 5418142, be incorporated herein by reference.
It is the composition of hydrogen peroxide with conversion of glucose that the detectable composition comprises a kind of, as glucose oxidase; One or several detects by the composition that is present in the hydrogen peroxide that glucose produced in the sample; With a kind of inhibitor.The composition that detects hydrogen peroxide can be peroxidase, be preferably the horseradish oxidase, and in course of reaction " indicator " of variable color.Indicator can be that a kind of oxidable dyestuff or dyestuff are right.In the presence of hydrogen peroxide, the oxidation reaction of peroxidase catalysis indicator.Last a kind of composition of reagent is an inhibitor, and it has postponed the generation of indicator oxidation stain reaction.
Detector bar is along its radial segments, and segmented mode is to make adjacent film sections have different inhibitor concentration.Each sections has a suction chemical examination district, when existing enough glucose at first to run out of all inhibitor, and oxidation indicator then, so when causing distinctive change color, the just variable color of chemical examination district.Therefore the variable color of a certain specific region just demonstrates glucose threshold concentration in the original blood sample.Along the detector bar specific direction, the inhibitor concentration of each sections raises gradually, and this is corresponding with the glucose threshold concentration that progressively increases.The concentration of indicator also is like this in all sections.The balance of other inhibitor/indicator also is possible in principle.
For a kind of concrete detection sample, if the inhibitor concentration scope of sections is suitable, after the reaction of adjacent chemical examination district and analyte, one of them variable color, and adjacent with it another is with regard to nondiscolouring.This result shows that concentration of glucose equals the required threshold concentration of this transformation region variable color at least in the sample, and less than the required threshold concentration of adjacent chemical examination district's variable color.
In order to carry out blood sugar monitoring, optionally timing agent sections coating form the porous matrix that comprises bar-scribble detectable-composition, also have glucose in addition.Under the drying regime, the reagent chemistry is not activated by glucose, and when sample be coated in detect to go up after, timing agent coating is by hydration, the glucose in the coating makes indicator generation variable color after at the fixed time.Preferably, glucose content substantially exceeds and overcomes inhibitor effect institute expense in the timing agent.At this moment, the length of required time or weak point depend on the many of inhibitor content or few.Change color in detector bar and the timing agent can perhaps be used the catoptrical variation of optics instrument detecting directly by naked-eye observation.
Description of drawings
Fig. 1 is a direct reading reagent detector bar matrix skeleton view of the present invention.
Fig. 2 is a direct reading reagent detector bar sample face of the present invention baseplane cut-open view.
Fig. 3 amplifies fragment for the perspective internal view that cut Fig. 2 test section.
Fig. 4 is the sectional view of Fig. 2 detector bar along the 4-4 line.
Fig. 5 is the bottom plan view of Fig. 2 detector bar.
Fig. 6 is a top plan view, is depicted as the detection faces of Fig. 5 detector bar.
Fig. 7 is Fig. 6 detector bar behind the last sample.
Fig. 8 is the sectional perspective view of the another kind of embodiment of Fig. 2 detector bar.
Fig. 9 is the bottom plan view of Fig. 8 detector bar.
Figure 10 is the top plan view of Fig. 8 detector bar.
Figure 11 is the sectional view of Figure 10 detector bar along the 11-11 line.
Embodiment
The present invention is the direct reading reagent detector bar that is used for measuring the biological fluid analyte concentration.It is the porous matrix that combines detectable that the key of this detector bar is formed, and analyte produces corresponding change color to this detectable in the biological fluid samples on the detector bar to being coated in.
The substrate that matrix can be unified composition or coating can be isotropic or anisotropic.It has one to keep supplying sample face and detection faces of observing variable color that sample is used.Matrix optimization is anisotropic film; The anisotropic membrane that more preferably has the broad pore diameter range.For example, the bore diameter gradient that extends in film is from about 0.1 micron to about 150 microns.In the macropore one side, preferred pore diameter range is about 30 microns to about 40 microns.In the less one side of membrane aperture, void volume is less relatively, and the pleurodiaphragmatic in terspace material generally is quite dense, generally can reach 20% of film thickness in one deck.Preferred pore diameter range is about 0.1 micron to 0.8 micron in this layer, specifies the aperture preferably to be about 0.3 micron.When biological fluid is coated on the sample face, sample when seeing through film the hole of process constantly diminish.Solid such as red blood cell just can not further see through behind the somewhere in arriving film basically.The sample surplus also contains lysed glucose, can see through to arrive detection faces.It is very fast relatively that the anisotropy of film and/or the use of separated component (hereinafter to some extent discuss) make sample pass the flow velocity of film, even if simultaneously also in the filtration of carrying out solid constituent.
When sample passes matrix, the reaction of sample and reagent generates light absorbing dyestuff or decomposes in the void volume near detection faces, thereby actually the reflectivity of matrix is exerted an influence.
Polysulfones and polyamide (nylon) are the base starting material examples that suits.Also can use the suitable polymkeric substance of other character.Polymkeric substance is handled through modification can introduce the functional group that other can provide charged structure, and making stromal surface can be neutral, positive or negative.
The preparation method who forms the porous raw material of matrix is preferably need not carry nuclear (supporting core) and prepare polymkeric substance.Such matrix for example is from Memtec, Inc, Timonium, the anisotropy polysulfone membrane of MD..Usually used thickness preferably uses about 115 to 155 microns matrix less than 200 microns matrix.Especially when matrix is nylon or anisotropy polysulfones, more preferably 130 to 140 microns of thickness.
The method of handling film with detectable can be that film is dipped in the reagent mixture of ingredients, makes film saturated.Preferably, at least some compositions are to be coated on the film in order.Excess reagent can be removed with mechanical means, with air knife (air kuife), scalpel or glass bar.Make the film drying then.Reagent is easy to be enriched near aperture (detection) face of film.
Detectable is formed and is comprised that (i) makes conversion of glucose is the composition of hydrogen peroxide, (ii) detects the composition of hydrogen peroxide and (iii) suppresses the composition that hydrogen peroxide detects composition.Reagent is optional further to comprise a kind of separated component, and this separated component makes such as erythrocytic solid and is trapped in the matrix, can remove the solid constituent in the biological fluid effectively.Can also comprise supplementary element, reach hereinafter among the embodiment and discuss to some extent.
With conversion of glucose is that the preferred component of hydrogen peroxide comprises glucose oxidase, and this is a kind of enzyme that obtains from aspergillus niger or mould usually.Glucose oxidase and glucose and oxygen reaction generate gluconolactone and hydrogen peroxide.The optium concentration of glucose oxidase is relevant with the composition of indicator system.For example, if indicator system is MBTHSB-ANS (argumentation is hereinafter arranged), the suitable concentration range of glucose oxidase is 500-10000U/mL, and more preferably 700-2000U/mL most preferably is 1000U/mL.In general, glucose oxidase concentration is high more, and reaction is carried out soon more, and concentration low reaction more is slow more.
Reaction gained hydrogen peroxide and the composition reaction that detects hydrogen peroxide, this composition comprises a kind of peroxidase, the reaction between this enzyme selectivity catalyzing hydrogen peroxide and the indicator.Peroxidase makes hydrogen peroxide play the effect of oxygenant, can remove the various hydrogen atoms that are applied thing.The peroxidase that is suitable for can contain hematin, and this is a kind of protohemin from plant.Peroxidase from animal also is suitable for, and Tathagata is from the thyroid gland of animal.Horseradish peroxidase (HRPO) is that hydrogen peroxide detects an especially preferred component in the composition.
Preferably under the catalytic action of peroxidase, hydrogen peroxide directly or indirectly react generate or decompose a kind of in predetermined wavelength range light-absorbing indicator dye.It is preferably different with the wavelength of detectable generation strong absorption that indicator dye produces the wavelength of strong absorption.The oxidised form of indicator can be coloured, light color or colourless final product, and this final product makes matrix detection faces generation variable color.That is to say that it is to be faded in coloured zone that detectable indicates the method that analyte exists in the sample, perhaps make the achromatic region colour developing.
Be used for the 3-dimethylaminobenzoic acid (DMAB) that indicator of the present invention comprises (a) hydrochloric acid 3-methyl 2-[4-morpholinodithio quinoline ketone hydrazone (MBTH) combination; (b) 3 of the MBTH combination, 5-two chloro-2-hydroxy benzene sulfonic acids (DCHBS); (c) 4-hydrogen base antipyrine (4-AAP) and 5-oxo-1-are to sulfophenyl-2-pyrazoline-3-carboxylic acid (OPSP); (d) tolyl-diethanolamine (NDA) between 4-AAP and N-; (e) 2,2 '-azine group-two (3-ethyl benzo thiazole phenanthroline) sulfonic acid (ABTS); (f) 4-AAP and 4-methoxynaphthol; (g) pyrogallol red (PRG); (h) bromine pyrogallol red (BPR); (i) ACID GREEN 25 (AG); Or (j) (3-methyl-2-[4-morpholinodithio ketone hydrazone) N-sulphonyl benzene sulfonic acid-sodium (MBTHSB), combine 8-anilino-1-naphthalene sulfonic acid ammonium (ANS).Preferred MBTHSB-ANS.The out of Memory of relevant MBTHSB-ANS sees the United States Patent (USP) announced on October 8th, 1996 No. 5563031, is incorporated herein by reference.
Certain suppresses composition can postpone reaction between hydrogen peroxide and the indicator, for example can by reduction hydrogen peroxide or reduction-oxidation indicator.Inhibitor has some different modes of action basically.At first, inhibitor and indicator competition are slowed down the speed of indicator generation variable color.Secondly, inhibitor also may be noncompetitive, and indicator all inhibitor before actual generation variable color are consumed basically like this.Other the inhibitor mode of action also is possible.Inhibitor of the present invention is preferably noncompetitive.
The inhibitor that is suitable for has 2,3, the 4-trihydroxybenzoic acid; Propyl gallate; 3, the 4-dihydroxycinnamic acid; 3, the 4-4-dihydroxy benzaldehyde; Gallate; 5,6-diamido uracil; Ascorbic acid; Arabo-ascorbic acid.Preferred ascorbic acid; Therefore but ascorbic acid oxidation in solution must make it stable, just can carry out coatings of reagent.The preferred primary alconol of stabilizing agent is as ethanol, methyl alcohol or propyl alcohol.Preferred alcohol, particularly its concentrated solution, the i.e. higher ethanolic solution of 50% solution or concentration.
But although as the anisotropic membrane filtering red blood cell of preferred substrate and make them away from detection faces, in the detectable also to contain a kind of separated component alternatively.Separated component should be able to make the erythrocytic liquid that contains such as whole blood become colourless relatively fluid by red blood cell is sequestered on the matrix.Be used for separated component of the present invention and include but not limited to polyglycol, poly-(methyl vinyl ether/maleic acid) acid anhydride, polypropylene glycol, polystyrolsulfon acid, polyacrylic acid, polyvinyl alcohol (PVA) and polyvinyl sulfonic acid, its pH is between 4.0 to 8.0.The content of this separated component depends on its electric charge and molecular weight, is embedded in other composition in the matrix, pH and the aperture and the dried residual moisture of matrix of matrix in the matrix.Those skilled in the art are easy to determine these parameters.For example if separated component with polypropylene glycol (as from BASF, Wyandoffe, the PPG-410 of MI), its content is preferably 2-30% w/v (W/V), more preferably 8-10%W/V.Also but working concentration is other separated component of 2-30%W/V.The separated component of polymerization can immerse or be embedded in the matrix or make film in preparation process.
Some water soluble salt also can separating blood constituents.The salt of the separating blood constituents that is suitable for has citrate, formates and sulfate, and some acid, as amino acid, citric acid, phytic acid and malic acid No. 3552928, the United States Patent (USP) of announcing on January 5th, 1971 of M.C.Fetter (for example referring to).An advantage using separated component be since it from biological fluid, can remove solid basically, as red blood cell, the metachromasia of detectable is disturbed with regard to less background colour detecting the position.
In matrix, also can embed colour developing and the readability that other one-tenth assigns to strengthen detector bar, keep the integrality and the fastness of matrix.For example, can comprise salt and/or buffer system in the detectable, help the separation of dyestuff in the matrix.Buffer system for example can contain citrate, and solution concentration is 0.01M to 1.0M, is preferably 0.1M.Also available other buffer system.
The also available compound of giving the hydrophilic compound of matrix or playing stabilizer function is white as the hydrolysis dawn.This compounds for example includes but not limited to white, polypeptide of pure dawn of ox blood and small-molecular weight dawn white matter, as Crotein SPA (CROD, Inc, New York, N.Y.).The used concentration of this compound is 1mg/mL to 100mg/mL for example.If use Crotein, concentration is preferably 300mg/mL.
Also can comprise other stabilizing agent and antiseptic in the matrix coating.For example available ethylenediamine tetraacetic acid (EDTA), diethylene-triamine pentaacetic acid (DTPA) and related compound, its concentration is 0.01mg/mL to 10mg/mL for example.The effect of antiseptic is help inhibitor stable.
Some indicator (as BPR) have in matrix the trend that moves, this be people do not wish to see.If use a kind of like this indicator, to add a kind of ion-pairing agent for preventing to move.For example, polyethyleneglycol derivative, as Polyquart (H) commodity (Henkel, Inc, Ambler, PA) especially suitable because can facilitate the formation of ion pair between their indicator and other matrix components.
When indicating the existing of analyte with color producing reaction (as MBTHSB-ANS), can add surfactant, make color obvious, strengthen contrast with colourless environment.
The present invention also can be with an organic solvent when implementing, and can be comprised in the composition of matrix detectable, has only them compatible with matrix and detectable composition certainly.The organic solvent that may be suitable for comprises chloroform, acetone, alcohols, methylene chloride, diethyl ether and sherwood oil, acetonitrile and their potpourri.Preferred especially 70% ethanol water when enforcement is of the present invention.
The detectable that is coated on the matrix or immerses in the matrix is not uniform on the detector bar surface.On the contrary, reagent preferably is used on the matrix by band or " sections " of series of parallel in the detector bar width.The inhibitor concentration of adjoining sections progressively raises.Sections has water absorptivity chemical examination district.As long as concentration of glucose is even as big as overcoming the exposure level of inhibitor in the chemical examination district in the blood, detectable just in the chemical examination district with the glucose response variable color.Therefore, make that concentration of glucose progressively increases in the continuous required sample of chemical examination district variable color.
Alternatively, will chemically examine one of district as the timing agent, can indicate each chemical examination district go up reagent and glucose response the time enough of process.The timing sections of matrix be coated with or soak to consist of the composition of the outer glucose of detectable.Because the detectable purpose is and glucose effect generation variable color, the two is combined and do not cause that change color needs careful operation.Must add the inhibitor that substantially exceeds the clocking capability aequum for this reason.After adding contains glucose solution, the speed of control timing sections drying.In the practical operation, the solution that at first will contain buffer system, stabilizing agent and enzyme is coated on the film, the dry ground floor that forms of coating.Be coated with the second layer with the solution that contains indicator, inhibitor and glucose then.Carry out parameter in advance and determine, knit speed (web speed), oven temperature, air-flow, reach the coating solution deposition as net, and inhibitor and/or concentration of glucose are suitably adjusted.Also having a kind of method is not directly to be coated with the second layer, neither preferable methods, and be in independent online formation second coating, again it is covered on ground floor.
After sample was coated on the detector bar, the aquation of timing sections composition was carried out color producing reaction.Timing sections generation variable color required time is decided by the character of temperature and detectable then, is especially decided by inhibitor concentration, glucose content and aquation and oxygen rate of diffusion.
The timing agent variable color time both can decide according to concentration of glucose in the sample, also can be irrelevant with this concentration.By adding excessive glucose in the timing agent, the variable color time has just had nothing to do with the concentration of glucose of sample basically.If add a small amount of glucose in the timing agent, the variable color time is just depended on the glucose in the sample, that is to say, concentration of glucose is big more in the sample, and timing agent variable color is fast more.Concentration of glucose is preferably greater than 1500mg/mL in the timing agent, make the timing agent basically with sample in concentration of glucose irrelevant, the latter's scope is 40-400mg/dL.It is the composition (as glucose oxidase) and the excessive glucose of hydrogen peroxide that timing sections composition comprises the excessive conversion of glucose that makes.Timing agent composition also should contain and equate with sections as a result or than more inhibitor, and the inhibitor that sections contained is maximum (corresponding be that glucose readings is the highest) as a result.
The timing agent also has the important quality control effect, and when detector bar was damaged because of contact wetting, the timing agent made it become transparent.Detector bar must keep dry before use, and this is to be to decompose behind composition (normally enzyme) contact wetting of hydrogen peroxide because make conversion of glucose.Therefore if the prior contact wetting of detector bar just has been damaged.If but the user does not perceive this, the result that may must make mistake with this detector bar.After containing the timing agent in the not excessive detector bar, contact wetting makes timing agent variable color, reminds user's detector bar to damage, can not use again.
The out of Memory of relevant timing agent sees the unsettled U.S. Patent Application Serial of submitting on September 3rd, 1,996 08/706753, is incorporated herein by reference.
Except the matrix that contains reagent, detector bar of the present invention also contains the bottom that carries matrix.Preferably a kind of thermoplastic sheet of bottom is more preferably a kind of polyester, general thick about 0.05-0.2mm, and this bottom has a hole, and sample is by the sample face of sample on this hole to matrix.Blood sample comes along the matrix radial distribution from last sample hole.Bottom generally is opaque, if like this, can from the suitable distance in sample hole one or several transparent fenestella is set, can confirm that by the sample outward appearance of observing in the fenestella sample is to detector bar on the existing capacity sample.
Blood will be through the middle layer between bottom and film when chemical examination district distributes from last sample hole, the middle layer stick to alternatively two-layer between.The preferably a kind of thermoplastic sheet in middle layer is more preferably a kind of polyester, general thick about 0.05-0.2mm.In one embodiment, the slit directs sample in the middle layer radially arrives each chemical examination district in the non-water absorptivity path of upper edge film at detector bar.Recess in the middle layer is consistent with the chemical examination district, and in fact each chemical examination district is surrounded by the middle layer wall.In another embodiment, there is the hole that is actually rectangle of a lengthening in the middle layer, and the sample of guiding film near surface arrives the chemical examination district.The rectangular opening width is generally 0.5-3mm.
Form the preferred structure in non-water absorptivity path on the film by the pore structure of destroying film.Heating can be accomplished this point, and type of heating is that direct-heating type uses laser or ultrasound wave, the preferred method that also has pressurization, but preferred method is an extrusion.Make film except the chemical examination district, all become non-absorptive (but still being hydrophilic) by extruding.In an embodiment of the invention, squeeze film between two flat boards prevents that with matrix the chemical examination district is extruded simultaneously.Pressure is preferably at least 6 Tons per Inch 2 (80000 kPas).Alternatively, flat board can be heated to more than 110 ℃.Preferred pressure and time will be depended on the extruding mechanism and the residence time certainly, and the film parameter.Can determine optimal value by conventional test.In the embodiment as described below, film pushes through this method, makes chemical examination district extend to bottom, in the film in addition with the middle layer of recess.
For measuring accurately, the blood volume that offers each chemical examination district is preferably reproducible.If recess is distinguished around chemical examination fully, and suppose can realize liquid sealing between middle layer and bottom and squeeze film that each chemical examination district will form (cylindrical shape) volume of a sealing so, its perisporium is the middle layer, and two ends are rete and bottom.But also have a distribution channel, sample is sent to each chemical examination district along detector bar.Preferably at bottom the plurality of rows pore is arranged, arrange in the district along chemical examination, helps sample filling channel and chemical examination district equably.The pinpoint accuracy of measuring requires the sample of distribution channel to each chemical examination district supply fixed volume, but the measurement period that sample began after 90 seconds on blood at least-no longer supply sample in about 1 or 2 minute.Because initial sample volume is variable, preferably exists in an absorption layer at the two ends of film, can remove the excessive sample of distribution channel end.Absorption layer can say also that at channel end sample is along detector bar capillary action radially.The non-knot fabric of knitting known in the art can constitute preferred absorption layer.
In another embodiment of the invention, come press mold and cover plate with roller.Cover plate is provided with the hole, will chemically examine the district and hold wherein, and the chemical examination district that is not extruded extends in the hole.Need not matrix in this embodiment, squeezing action is preferably finished by roller, and working pressure is at least 10001b (4450N).Bearing of trend that it should be noted that chemical examination district in the present embodiment is opposite with above-mentioned embodiment.Because sample is open state and is attracted to the upper strata, bottom is no longer established vent port.The middle layer has one to be the hole of rectangle basically in the present embodiment, and the guiding sample arrives the chemical examination district.Owing to go up in this embodiment near " high concentration glucose " chemical examination district end that the sample hole is positioned at detector bar, near the detector bar other end, only need an absorption layer to get final product.
Be apparent on the film detection faces by the caused change color of glucose in the sample to be tested.Extend in the embodiment of bottom in the chemical examination district, way is that the upper strata with the hole of arranging along the chemical examination district is covered on the detection faces of film easily.The effect in hole is to be convenient to observe variable color and to make oxygen arrive reactive site.If extend round about in chemical examination district, as mentioned above, defined the chemical examination district in the hole of extrusion process at the middle and upper levels.In two kinds of situations, the preferably a kind of thermoplastic sheet in upper strata is more preferably a kind of polyester, general thick about 0.05-0.2mm.The upper strata can for example be bonded on the film with a kind of bonding agent.If bonding agent disturbs the glucose measurement reaction, bonding agent preferably is limited in the non-absorption region of film and uses.If but bonding agent does not disturb this reaction, its position is not very important.
Because the chemical examination district of containing preferred reagent contact slowly variable color of back with light or oxygen, also since optional timing agent to moisture-sensitive, preferably detector bar is wrapped in the opaque overcoat of oxygen flow not and waterproof, as the foil paper that seals.If detect is single packing, and detector bar in use can be stayed in the wrapping paper in Kaifeng.
With reference to accompanying drawing will the invention will be further described.Fig. 1 measures the matrix 10 of analyte content in the biological fluid for the present invention.Although be the arcuation bending among the figure, matrix 10 is soft in fact, is plane in use generally.Matrix comprises sample face 12, for sample usefulness and detection faces 14 on the biological fluid, thereon or near the existence of the variable color of generation indication analyte.The generation of variable color is from analyte and the interaction of immersing the reagent in the hole 16.During concentration of glucose, near the aperture the sample face 12 is relatively large in measuring blood, and the aperture reduces near detection faces 14 time.Bore diameter gradient is used for catching red blood cell near sample face 12, makes the latter's color can not disturb the observation of the change color that the indication analyte is existed.
Three parallel segment a, b, c are as shown in the figure.Each continuous sections is than the previous inhibitor that progressively increases that contains.In preferred embodiment, as shown in the figure, add reagent on the film in the parallel segment after, the part except the analyte reagent reacting takes place on the film is pushed.Planimetric map 2 and skeleton view 3 fragments of amplifying have illustrated the embodiment of this kind mode, i.e. water absorptivity chemical examination district one is arranged in the single area one of each parallel segment and the non-suction zones that is extruded.
Fig. 2 is the bottom plan view of sample face 12 with the broken section of absorption layer 20,22 of film 10, is stamped middle layer 24 and bottom 26 on the film.Preferred film 10 and absorption layer 20,22 are being carried by a top layer, do not show among the figure.Absorption layer 20 and 22 is preferably placed at the end (beyond dotted line A and the B) of film, absorbs to surpass the blood sample of measuring aequum.This measurement aequum must be enough to make sample to arrive each chemical examination district, and the timing agent, if any.In general, the contained chemical examination of detector bar district does not seldom need a lot of samples, but the scope of the dextrose equivalent that is detected is less, and/or accuracy is relatively poor.Mark 9 suction zones among Fig. 2, represent 8 chemical examination districts (numbering 1-8) and 1 timing agent (T), neither need unacceptable great amount of samples, also have enough measurement ranges and accuracy.There is a recess 28 in middle layer 24, aligns with the last sample hole 30 on the bottom 26.Sample from the last sample hole 30,24 centre gangway 32 is drawn towards each chemical examination district and timing district to sample along the middle layer by capillary action, and any excessive sample is absorbed in absorption layer 20 and 22.Observe by optional fenestella 34 and 35 and can confirm that quantitative sample is used to measure.Form sealing between the sample face 12 of preferred interlayer 24 and film, sample just can directly not flow between the chemical examination district that adjoins like this.
Fig. 3 is the skeleton view fragment of amplifying, and expresses from 6,7,8 three chemical examination districts of bottom 26 directions and the middle layer 24 that separates with finger.Optionally adhesion layer 24a is bonded at middle layer 24 on bottom 26 and the film 10.Vent port 40 on the bottom 26 helps sample flowing in detector bar.Face the hole of suction zones on the top layer 36,, can supply the usefulness of the variable color observation of suction zones, the required oxygen of metachromasia is entered as 38.Optionally adhesion layer 36a is bonded at top layer 36 on the detection faces of film 10.
The sectional view that Fig. 4 sections along the 4-4 line for Fig. 2 is expressed top layer 36, and layer shown in Figure 2.Vent port on the bottom 26 as 40, over against chemical examination district and timing district, helps sample to be full of each space on every side, zone.The space that is full of is surrounded by film 10, middle layer 24 and bottom 26.It should be noted that column chemical examination district extends to bottom 26, the minimum separation degree between chemical examination district and the bottom generally only is about 12 microns.For clarity sake, the diagram separation has been amplified.
Fig. 5 is the baseplane of detector bar of the present invention, in be the legend that last sample hole 30 and guides user are passed through sample on this hole.Observe by transparent fenestella 34 and 35, can confirm that the capacity sample has been suffered to detector bar by last.
Fig. 6 is the planimetric map of detector bar top layer 36, and this detector bar carries out overcorrect with concentration of glucose to the chemical examination district.
Figure 7 shows that the detector bar of Fig. 6, be blood sample by on to opening 30 (Fig. 2) afterwards, sample comes along centre gangway 32 diffusion, the glucose in the sample with the chemical examination district in reagent reacting.Because inhibitor is minimum in the chemical examination district of bottom, also just variable color at first.Be second then, be the 3rd regional variable color after again.The ring nondiscolouring on top, this be because the glucose in the sample very little.Because having passed through time enough makes timing agent 42 variable colors, detector bar can carry out reading.Result shown in Fig. 7 shows the sample concentration of glucose at least more than 120mg/dL, but is less than 150mg/dL.Any time after 42 variable colors of timing district can be carried out reading.Noticeable is among Fig. 7 because of the variable color that takes place with glucose response be from colourless become coloured.But, system also may be such principle of work, i.e. the oxidation reaction of glucose initiation has been destroyed indicator dye, and correspondingly color also becomes colorless from coloured.
Fig. 8 is the sectional perspective view of the another kind of embodiment of detector bar of the present invention.Bottom 126 has a last sample hole 130 of introducing blood sample.Not as Fig. 2 embodiment, last sample hole 30 is positioned at the middle part of detector bar (from an end to the other end), is preferably placed at a end near detector bar and go up sample hole 130 among this figure, and the chemical examination district and the optionally timing agent of indication high concentration glucose are arranged on this end.To go up sample also is positioned this end two benefits is arranged.The first, reduced blood arrival " high sugar " chemical examination district's (response time is the longest) used time, also just reduced the required time of glucose measurement.The second, reduced the variability of timing agent, because being actually directly, goes up to the timing agent by sample, also just eliminate blood and arrived the used temporal variability of timing agent.There is the slot 132 of a lengthening in middle layer 124, and its length and detector bar are suitable, start from an otch, and this otch is corresponding with last sample hole 130, faces sample hole 130.The flow through detector bar length of film 110 of slot guiding blood sample flows to absorption layer 120.Because of sample process film 110, part is deposited in timing agent T ' and eight the chemical examination districts (numbering 101-108).Observe timing agent and chemical examination district by the relative hole of top layer 136.Observe the blood outward appearance by transparent fenestella 135 and can confirm that existing enough samples are used for measuring.
Fig. 9 is the bottom plan view of Fig. 8 detector bar, and wherein guides user is by the hole 130 of bottom, and the legend (as shown in Figure 5) that (with the relative opening 128 in middle layer) goes up sample is omitted.
Figure 10 is the planimetric map of top layer 136, is illustrated as the correction of timing agent to the chemical examination district.
The sectional view of Figure 11 for sectioning along 11-11 line among Figure 10 shows top layer 136, film 110, middle layer 124 and bottom 126.Arrow indicates the direction of introducing sample from the hole 128 in the hole 130 of bottom 126 and middle layer on the other side 124.It should be noted that column timing district T ' extends up to the hole 138 that preferably enters correspondence, this hole faces timing district T ', is one of nine holes on the top layer 136, and the hole on the top layer is facing to corresponding timing agent and chemical examination district.
For better understanding the present invention, the following example further specifies various embodiment of the present invention.Embodiment does not play the restriction of any way.
Example 1 BPR indicator
Prepare following solution: distilled water 83.5g1% (w/w) EDTA Na 223.8g aconitic acid 6.0gNaOH (Gu) 2.2gCrotein SPA 4.2g imidazoles 0.6g mannitol 3.0g5% (w/w) Surfactol Q1 3.0g adjusting pH to 4.80 ethanol 40.0gPPG-410 5.6g enzyme solutions 28.0g
Enzyme solutions 0.2M 27.0g glucose oxidase 165,000UHRPO 340,000U
Memtec BTSH55 film is immersed this solution, it is coated with in the above, excessive part is removed with glass bar.The film that applied is dry in the floating drying of 180F, middling speed air-flow, this net was dried in 20 seconds basically.Roll net, prepare to apply the second layer, as described below.Prepare following solution: ascorbic acid (inhibitor) stock solution thinning agent distilled water 190g 370g1%EDTA Na 255g 107gBPR 0.36g 0.71gPoly Quart  H 6g 11.8gPPG-410 14.2g 27.8g ascorbic acid 1.37g-ethanol 243g 477g
Timing agent solution thinning agent (above-mentioned each prescription) 120g ascorbic acid 0.885g glucose solution *17.25g
*Glucose solution is the 16.0g/dL aqueous solution of mutarotation 24 hours, refrigerated storage.
Make the dilution of following stock solution: 0.0405: 1,0.108: 1,0.236: 1,0.369: 1,0.569: 1,1.260: 1.Inhibitor concentration progressively raises, and the concentration of glucose that this and chemical examination district are reported progressively raises and matches.These solution and timing agent solution are coated on the macropore face that carries enzyme membrane Face to face, make deposition about 1.2 * 10 on every square millimeter of film -4ML.With moistening about 15 seconds of film, then according to being coated with condition same in the enzyme step and carrying out drying with above-mentioned.The result shows that the timing agent was at about 70 seconds internal reactions, and 95% situation is between 64 and 79 seconds.
Example 2 MBTHSB-ANS indicator
Prepare following solution: HPLC water 1500mL citric acid 16.92g natrium citricum 20.88g mannitol 15gEDTA=sodium 1.26gGantrez S95 6.75gCrotein SPA 36g glucose oxidase 1.69MUHRPPO 1.5MUCarbopol 910*The 75mL disodium citrate *225mL *11% acetonitrile solution *0.1M, pH5.0
Memetc BTS 35 films apply in groove, and big hole surface is contacted with coating solution; The same, excess solution is removed with glass bar.With example 1, will roll after the film drying.
Make following solution: solution A (indicator) solution B (wetting agent) 70% (v/v) ethanol 2819mL Maphos  60A 41gMBTHSB 2.98g 70% (v/v) ethanol 205mL (NH 4) ANS 25.83mL solution B 205mL2%DTPA 51.25mL
Solution D, (timing agent) solution C, (ascorbic acid liquid storage) water 53mL water 115mL ascorbic acid 8.75mL ascorbic acid 4.58g ethanol 123mL ethanol 267mL adds to 175mL glucose solution 40.5mL with 70%EtOH
Every part of inhibitor solution all is fixed on 263mL with solution A.Different chemical examination districts, 70%EtOH: the solution C ratio also from 58.9 to 0.200 does not wait, and making 70%EtOH+C all is 87.5mL adding fashionable in solution A to all inhibitor.So only effectively change the concentration of inhibitor in every part of solution.To contain solution and the timing agent solution (solution D) that inhibitor concentration progressively raises is coated on the macropore face of film Face to face.Regulate deposition, make on every square millimeter of film to reach-8 * 10 -5The mL inhibitor.Film is the method drying as above, and just dry the hysteresis applied about 1.6 minutes.The result shows, the timing agent is at about 60 seconds internal reactions, is the function influence of the glucose of 30 to 55% blood or 78 to 420mg/dL and be not subjected to hematocrit.
Those skilled in the art considered that how above-mentioned explanation and embodiment only implement for explanation the present invention, do not play any restriction.Under the prerequisite that does not deviate from the scope of the invention and spirit, can the particular content in the literary composition be changed.

Claims (31)

1. a lengthening multilayer reagent detector bar that is used to measure the biological fluid samples analyte concentration that is coated with thereon comprises
A) bottom, this bottom has a hole of accepting the perforation of sample;
B) rete, in the face of bottom simultaneously is the sample face, relative another side is a detection faces, this rete is distributed with a large amount of water absorptivity chemical examinations district along its length direction, separated by non-suction zones each other, contain a kind of reagent that variable color can take place with the analyte reaction in the film, this reagent is formed and is comprised
I) react the first kind of composition that generates hydrogen peroxide with analyte;
Ii) with second kind of composition of hydroperoxidation generation variable color; With
The third composition that iii) suppresses second kind of composition variable color;
C) middle layer between bottom and rete;
D) measuring apparatus that makes sample distribute and come along detector bar, this device are formed and are comprised the fluid transhipment passage that forms in the middle layer, and the guiding sample arrives water absorptivity chemical examination district through the film surface; Inhibitor concentration is raising in a predefined manner from detector bar first end a distance, therefore if variable color takes place, the also necessary corresponding rising of the analyte concentration that is contained in the sample, wherein behind sample on the detector bar, variable color takes place in one or several chemical examination district, and indicating the concentration of analyte in the sample from first end transformation region farthest, described first end is an end that at first contacts with the biological fluid sample body.
2. the detector bar of claim 1, analyte wherein is a glucose.
3. the detector bar of claim 1, biological fluid wherein is a blood.
4. the detector bar of claim 1, bottom are wherein formed and are comprised a thermoplastic sheet.
5. the detector bar of claim 4, bottom are wherein formed and are comprised polyester.
6. the detector bar of claim 1, bottom wherein further contain the hole of the perforation that faces the chemical examination district in a large number, the end that described first end at first contacts with the biological fluid sample body.
7. the detector bar of claim 1, bottom wherein has a transparent part, and to guarantee that sufficient sample size is arranged, this transparent part is positioned at from sample receiving orifice a distance.
8. the detector bar of claim 1, rete are wherein formed and are comprised an anisotropic perforated membrane, and the hole on the film is bigger near the sample face, less near detection faces.
9. the detector bar of claim 8, biological fluid wherein is for containing erythrocytic whole blood.
10. the detector bar of claim 9, the selection in aperture wherein will make that red blood cell is trapped in the film in the whole blood sample.
11. the detector bar of claim 8, film are wherein formed and are comprised polysulfones.
12. the detector bar of claim 1, fluid transhipment passage wherein is rectangular basically.
13. the detector bar of claim 1, first kind of composition wherein comprises glucose oxidase.
14. the detector bar of claim 1, second kind of composition wherein comprise that a kind of peroxidase and the metachroic indicating dye of a kind of oxidation or dyestuff are right.
15. the detector bar of claim 14, peroxidase wherein are horseradish peroxidase.
16. the detector bar of claim 14, indicator dye wherein or dyestuff are to being the 8-anilino-1-naphthalene sulfonic acid ammonium (MBTHSB-ANS) of (3-methyl-2-[4-morpholinodithio quinoline ketone hydrazone) N=sulfonyl benzene sulfonic acid one sodium combination.
17. the detector bar of claim 1, the third one-tenth wherein is grouped into and comprises ascorbic acid.
18. the detector bar of claim 1, reagent wherein further comprises a kind of separated component, and this separated component is selected from the group of being made up of following material: polyglycol, poly-(methyl vinyl ether/maleic acid) acid anhydride, polypropylene glycol, polystyrolsulfon acid, polyacrylic acid, polyvinyl alcohol (PVA) and polyvinyl sulfonic acid.
19. the detector bar of claim 1, middle layer are wherein formed and are comprised a kind of thermoplastic sheet.
20. the detector bar of claim 1, middle layer are wherein formed and are comprised polyester.
21. the detector bar of claim 1, suction zones wherein and non-suction zone have constituted the not crimping section of rete respectively and have been extruded part.
22. the detector bar of claim 21, not extruding suction zones wherein are column basically, the basal plane of each post is on film, and relative end face is on bottom.
23. the detector bar of claim 21, not extruding suction zones wherein are column basically, the basal plane of each post is on film, and relative end face is on top layer, and this top layer is positioned at the outside of rete.
24. the detector bar of claim 1 further comprises a top layer, this top layer contacts with the rete top surface, and this top layer has the hole of the perforation relative with the chemical examination district.
25. the detector bar of claim 24, rete wherein is bonded on the top layer.
26. the detector bar of claim 25, rete wherein is bonded on the top layer with a kind of bonding agent, and this bonding agent is limited in the non-water absorptivity zone of rete and uses.
27. the detector bar of claim 1 further comprises an absorption layer, that end in contact of the most close detector bar first end on this absorption layer and the film.
28. the detector bar of claim 1 further comprises an absorption layer, each end of this absorption layer contact rete.
29. the detector bar of claim 1 further contains a timing agent composition, this timing agent is made up of a chemical examination district, and this chemical examination district also comprises a certain amount of glucose except that reagent, this time count the schedule time of agent behind sample on the detector bar and make this chemical examination district variable color
30. the detector bar of claim 29, the hole of the perforation of accepting sample wherein near on the detector bar away from that end of first end.
31. a method of measuring analyte concentration in the biological fluid samples comprises the following steps:
(a) sample on the reagent detector bar, this detector bar comprises
I) bottom, this bottom has a hole of accepting the perforation of sample;
Ii) rete, have a sample face in the face of bottom, this rete comprises a large amount of water absorptivitys chemical examinations district, and each chemical examination district is with contain after the fluid of the analyte of scheduled volume contacts at least all can variable color, the closer to detector bar first end, cause that the amount of the analyte of chemically examining district's variable color is just many more;
Iii) measuring apparatus makes sample arrive each chemical examination district from the hole that connects along predetermined non-water absorptivity path profile,
(b) by observing the concentration of measuring analyte from detector bar first end variable color chemical examination district farthest.
CNB971297886A 1996-12-31 1997-12-31 Multilayer reagent test strip and method for testing using same Expired - Lifetime CN1135388C (en)

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US08/779,735 US5843691A (en) 1993-05-15 1996-12-31 Visually-readable reagent test strip
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